Peripheral arterial insufficiency, often apparent as intermittent claudication, is an important cardiovascular disease that leads to exercise intolerance and loss of limb function. Enhanced physical activity represents one useful treatment and leads to an increased exercise tolerance. We hypothesized that the improved performance evident after increased physical activity is due to two factors: 1) cardiovascular adaptations which improve muscle blood flow by a) development of collateral vessels, and b) a redistribution of blood flow within the affected limb; and 2) peripheral adaptations with-in the affected muscle that improve blood-tissue oxygen exchange by a) an increased mitochondrial content, and b) an increased capillary network. We have established that both factors are induced by exercise training in an animal model of peripheral arterial insufficiency. Our rat model is created via bilateral stenosis of the femoral artery, sufficient to limit active hyperemia but not alter resting blood flow. We now propose to further our understanding of these cardiovascular and peripheral adaptations and proceed to evaluate the mechanisms responsible for the improved muscle performance. Animals are trained by treadmill running. Adaptations in collateral-dependent blood flow will be evaluated during treadmill running. Blood flow to all muscles of the hind-limbs, including individual muscle fiber sections, will be determined with labeled microspheres. We will also evaluate the influence of progressive vascular occlusion (ameroid constrictor), the retention of adaptations during detraining, and potentiation of adaptations due to heparin. Peripheral adaptations will be evaluated during contractions, using an isolated perfused hindlimb preparation. Blood-tissue exchange properties (PS product, transit time) and modified mitochondrial function (with a selective tight-binding inhibitor of electron transport) will be assessed. Flow-limiting perfusion conditions will be used to probe the functional impact of the improved blood-tissue oxygen exchange found in the trained muscle. These unique studies will provide essential information, important to the understanding of intermittent claudication and its clinical management.